1. Field of the Invention
The invention relates to crystalline polymorphs of methanesulfonic acid addition salts of Imatinib and to the synthesis thereof, and in particular to the synthesis of the α-crystal form of Imatinib mesylate.
2. Description of the Related Art
Imatinib, 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-yloamino]phenyl]benzamide, has been disclosed in the European Patent Application EP 0564409 A1 as a pharmacologically active substance having anti-tumor activity, especially useful in the treatment of diseases which respond to inhibition of tyrosine kinase receptors.
International Patent Publication WO 2004/026930 relates to the use of Imatinib or a pharmaceutically acceptable salt thereof for reducing inflammation. Although the use of many pharmaceutically-acceptable acid addition salts of Imatinib is mentioned including methanesulfonic acid salts of Imatinib, experimental studies are described in detail only with respect to the monomethanesulfonate salt thereof.
A novel crystal modification of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-piperidin-3-yl)pyrimidin-2-ylamino]phenyl]benzamide, i.e. the β-crystal form, has been described in the International Patent Publication WO 99/03854. The β-crystal form could be obtained, inter alia, from the less thermodynamically stable α-crystal form by triturating a suspension of the latter in a polar solvent, especially an alcoholic solvent, such as methanol. The β-crystal form could be also obtained directly from the free base by treating a suspension of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-yloamino]phenyl]benzamide with methanesulfonic acid in methanol, concentrating the obtained solution and inoculating it with seeds of the β-crystal form.
In WO 99/03854, a general observation was made that the α-crystal form of the methanesulfonic acid addition salt of Imatinib could be obtained, e.g., by precipitating out the salt from its solution in a solvent other than alcohol, such as methanol, and without adding any seeds of the β-crystal form. The method of preparing the α-crystal form, disclosed in Example 1 of WO 99/03854 is as follows:                (1) a suspension of the free base in ethanol is treated with methanesulfonic acid and the solution of the obtained salt is refluxed for 20 min.;        (2) the solution obtained as above is concentrated to a half of its initial volume and the precipitate that has formed is filtered at 25° C., to give the filtration product A;        (3) the filtrate is evaporated to dryness, the filtration product A is then added to the residue followed by appropriate volume of ethanol and water and the mixture is refluxed until completely dissolved;        (4) after cooling the solution slowly down to 25° C., the α-crystal form is isolated by filtration.        
However, failed attempts to reproduce Example 1 of WO 99/03854 by Inventors of the present invention have proven that the disclosure of WO 99/03854 is insufficient for preparing the α-crystal form selectively and in a reproducible manner.
On repeating the procedure of the Example 1 with the use of absolute ethyl alcohol (i.e., ethanol containing 0.1% (m/v) of water), Inventors of the present invention have found that the combined filter material A and the residue after evaporating the mother liquor does not completely dissolve in the specified volume of water and ethanol. Despite filtering undissolved crystals and cooling down the reaction mixture to room temperature results in readily crystals formation, comparison of their X-ray powder diffraction pattern with the data provided in WO 99/03854 evidences the formation of β-crystal form. On the other hand, in case of using ethanol containing 4.8% (m/v) of water, the solution concentrated to a half of its volume does not crystallize easily and the final solution of the salt does not crystallize without inoculation with the proper crystal form even after 36 hours after it has been cooled down to about 16° C.
Furthermore, one drawback associated with the process for preparing the α-crystal form, disclosed in the International Publication WO 99/03854, is that it requires several unit operations, such as isolation of crude methanesulfonate crystals from the reaction mixture, evaporating ethanol from the reaction mixture and re-suspending the methanesulfonate salt in the same solvent.
Moreover, Inventors of the present invention have found that without inoculating the reaction mixture with a proper crystal form, crystallization of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[4-pyridin-3-yl)pyrimidin-2-ylamino]phenyl]benzamide has a random nature, i.e., either the α-crystal form, the β-crystal form or mixtures thereof are obtained randomly without regard to the reaction conditions.
Therefore, it has been necessary to find a selective and reproducible method of preparing the α-crystal form of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[4-pyridin-3-yl)pyrimidin-2-ylamino]phenyl]benzamide, a method which would be suitable for use as a one-pot reaction.
The problem of the non-selectivity and non-reproducibility of the prior art methods has been solved by a process disclosed in the Polish Patent Application No. P-366885 filed Apr. 2, 2004, in which the reaction of equimolar amounts of methanesulfonic acid and 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]benzamide is carried out in ethyl alcohol or in a mixture of ethyl alcohol with another C1-C4 aliphatic alcohol; then an ester of a carboxylic acid and C1-C4 aliphatic alcohol is added to the reaction mixture, the reaction mixture is cooled down to the internal temperature A, seeded with the crystals of the α-crystal form and the resulting reaction mixture is left with stirring at internal temperature B for the time necessary for crystallization of the α-crystal form.
Although the method allows for obtaining the pure α-crystal form, it requires using two different solvents, the second of which (an ester of a carboxylic acid and C1-C4 aliphatic alcohol) causes precipitation of the acid addition salt from the reaction mixture. Furthermore, the method requires inoculating the reaction mixture with the seeds of the α-crystal form and the yield of crystallization hardly exceeds 80%.